A. Field of the Invention Reference
The present invention relates to compositions and methods for the prevention, reduction, and/or treatment of cardiovascular diseases with synthetic and naturally occurring polymethoxyflavone compounds derived, some of which are derived from limocitrin and quercetin.
These compounds include, but are not limited to, the following examples of limocitrin and quercetin derivatives:                limocitrin-3,7,4′-trimethylether (5-hydroxy-3,7,8,3′4′-pentamethoxyflavone)        limocitrin-3,5,7,4′-tetramethylether (3,5,7,8,3′4′-hexamethoxyflavone)        limocitrin-3,5,7,4′-tetraethylether (8,3′-dimethoxy-3,5,7,4′-tetraethoxyflavone)        limocitrin 3,7,4′-trimethylether-5-acetate        quercetin tetramethylether (5-hydroxy-3,7,3′,4′-tetramethoxyflavone)        quercetin 3,5-dimethylether-7,3′,4′-tribenzyl ether        quercetin pentamethylether (3,5,7,3′,4′-pentamethoxyflavone)        quercetin-5,7,3′,4′-tetramethylether-3-acetate        quercetin-5,7,3′,4′-tetramethylether (3-hydroxy-5,7,3′,4′-tetramethoxyflavone).        
Examples, but not limited to, of naturally occurring polymethoxyflavones for the purposes of the present invention include:                3,5,6,7,8,3′,4′-heptamethoxyflavone        nobiletin (5,6,7,8,3′,4′-hexamethoxyflavone)        tangeretin (5,6,7,8,4′-pentamethoxyflavone)        5-desmethylnobiletin (5-hydroxy-6,7,8,3′4′-pentamethoxyflavone)        tetra-O-methylisoscutellarein (5,7,8,4′-tetramethoxyflavone)        5-desmethylsinensetin (5-hydroxy-6,7,3′,4′-tetramethoxyflavone)        sinensetin (5,6,7,3′,4′-pentamethoxyflavone).        
B. Description of the Related Art
Limocitrin derivatives are a group of citrus-derived flavonoids that are naturally occurring in the plant or are chemically synthesized. 5-desmethylsinesetin is chemically synthesized form of sinensetin (Tatum, J. H. et al., Phytochemistry II, 2283-2288, 1972). Sinensetin occurs in trace levels in mandarin orange leaves (Sugiyarna, S. et al., Chem. Pharm. Bull., Volume 41, 714-719, 1993), and in orange and mandarin peel. Flavonoids are polyphenolic compounds that occur ubiquitously in foods of plant origin. The major dietary sources of flavonoids are vegetables, fruits, and beverages such as tea and red wine (Hertog, M. G. L. et al., J. Agric. Food Chem., Volume 41, 1242-1246, 1993). Flavonoids have been demonstrated to be the most potent dietary antioxidants and in light of the large dietary consumption, flavonoids make a major contribution to the antioxidant potential of the human diet. The main food sources of flavonols and flavones are black tea, onions, apples, herbs, and spices such as cloves and black pepper (Hertog. M. G. L., et al, J. Agric. Food Chem., Volume 40, 2379-2383, 1992).
The association between quercetin and cardiovascular disease has been studied in prospective cohort studies and cross-cultural epidemiological studies. Flavonol and flavone intake was inversely associated with mortality from coronary heart disease and to a lesser extent with incidence of first myocardial infarction. These effects were independent of known risk factors for coronary heart disease such as serum cholesterol, body mass index, blood pressure, smoking and intake of antioxidant vitamins, alcohol, and fat. Flavonol and flavone intake (mainly quercetin) was also inversely associated with stroke risk (Hertog et al., Lancet, Volume 324, 1007-1011, 1993; Keli et al., Arch. Inter. Med., Volume 154, 637-642, 1996). However, four thousand different types of flavonoids have been described and it is crucial that the active components be identified not only to make a positive impact on agriculture but also to more specifically use these nutraceuticals as anticholesterol agents and/or antithrombotic, anticoronary heart disease, antimyocardial infarction and/or antistroke agents.
In the United States, the complications of atherosclerosis account for about one half of all deaths and for about one third of deaths in persons between 35 and 65 years of age. Atherosclerosis, or the developments of atheromatous plaques in large and medium-sized arteries, is the most common form of arteriosclerosis. Many factors are associated with the acceleration of atherosclerosis, regardless of the underlying primary pathogenic change, for example, age, elevated plasma cholesterol level, high arterial blood pressure, cigarette smoking, reduced high-density lipoprotein (HDL) cholesterol level, or family history of premature coronary artery disease.
The risk of death from coronary artery disease has a continuous and graded relation to total serum cholesterol levels greater than 180 mg/dl (Stamler et al., JAMA, Volume 256, 2823, 1986). Approximately one third of adults in the United States have levels that exceed 240 mg/dl and, therefore, have a risk of coronary artery disease that is twice that of people with cholesterol levels lower than 180 mg/dl. Acceleration of atherosclerosis is principally correlated with elevation of LDL, or beta fraction, which is rich in cholesterol but poor in triglycerides, Elevation of HDL or alpha fraction, has a negative correlation with atherosclerosis (Castelli et al., JAMA, Volume 256, 2835, 1986). HDL exerts a protective effect and the ratio of total cholesterol to HDL cholesterol is a better predictor of coronary artery disease than the level of either alone. Total cholesterol levels are classified as being desirable (<200 mg/dl), borderline (200-239 mg/dl), or high (>240 mg/di) (Report of the National Education Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, Arch. Intern. Med., Volume 148, 36, 1988).
Advances in the study of cholesterol metabolism and coronary disease have initiated an era of increased emphasis on preventive therapy. New guidelines for the detection and treatment of high blood cholesterol in adults recommend that patients with high cholesterol levels or with borderline-high levels and two or more additional risk factors should have a measurement of LDL. LDL cholesterol levels are then classified as borderline-high risk (130-159 mg/dl) or high risk (>160 mg/dl). Dietary treatment is recommended for those patients with high-risk levels who have two or more additional risk factors. Drug treatment is recommended for all patients with LDL levels greater than 189 mg/dl and for those patients with LDL cholesterol levels between 159 and 189 mg/dl who have two or more additional risk factors. Among the many drugs that have been used to reduce serum cholesterol levels are cholestyramine, colestipol, clofibrate, gemfibrozil, and lovastatin.
Platelet-blood vessel interactions are implicated in the development of thrombosis. Flavonoids inhibit platelet aggregation and adhesion (Frankel et al., Lancet, Volume 341, 1103-1104, 1993). Flavonoids antagonize thromboxane formation and increase platelet cyclic AMP levels. This is important because flavonoids additionally scavenge free radicals and their antioxidant actions participate in their antithrombotic action (Gryglewski et al., Biochem. Pharmacol., Volume 36, 317-322, 1987). Drug treatment is recommended for patients with thrombosis and ischemic heart disease. The medical therapy comprises pharmaceutical drugs including, but is not limited to, aspirin (anti-platelet aggregating agents) and the combined use of beta-adrenergic blocking agents (e.g. propranonol, nadolol, timolol, etc.), nitrates (e.g., nitroglycerin) and calcium channel blockers (e.g., verapamil, nifedipine, diltiazem, etc.).
There remains a need in the art for methods and compositions for at least reducing the development of and/or treating vascular diseases. The present invention provides new compositions and methods directed to this need. The use of limocitrin derivatives, quercetin derivatives and/or, naturally-occurring polymethoxyflavones and mixtures thereof alone or in combination with a cholesterol-lowering drug has not been reported for at least reducing the development of and/or treating vascular diseases and disorders.